Abstract

The response to an innate immune challenge is conditioned by the
time of day, but the molecular basis for this remains unclear. In
myeloid cells, there is a temporal regulation to induction by
lipopolysaccharide (LPS) of the proinflammatory microRNA miR-
155 that correlates inversely with levels of BMAL1. BMAL1 in the
myeloid lineage inhibits activation of NF-κB and miR-155 induction
and protects mice from LPS-induced sepsis. Bmal1 has two miR-
155–binding sites in its 3′-UTR, and, in response to LPS, miR-155
binds to these two target sites, leading to suppression of Bmal1
mRNA and protein in mice and humans. miR-155 deletion perturbs
circadian function, gives rise to a shorter circadian day, and ablates
the circadian effect on cytokine responses to LPS. Thus, the molecular
clock controls miR-155 induction that can repress BMAL1 directly.
This leads to an innate immune response that is variably
responsive to challenges across the circadian day.

Item Type:

Article

Additional Information:

The definitive version of this article is available at DOI: 10.1073/pnas.1501327112 . This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1501327112/-/DCSupplemental.